Tag Archives: David Craig

Using a basic genetic difference between men and women, the Translational Genomics Research Institute (TGen) has uncovered a way to track down the source of a neurological disorder in a young girl.

TGen’s discovery relies on a simple genetic fact: Men have one X and one Y chromosome, while women have two X chromosomes. This women-only factor was leveraged by TGen investigators to develop a highly accurate method of tracking down a previously unrecognized disorder of the X-chromosome.

The study of a pre-teen girl, who went years with an undiagnosed neurobehavioral condition, was published today in the scientific journal PLOS ONE.

TGen’s findings were made within its Dorrance Center for Rare Childhood Disorders, where investigators and clinicians apply the latest tools of genomic medicine to provide answers for parents seeking to identify the disease or disorder affecting their child.

The scientists sequenced, or spelled out in order, the complete genetic codes of DNA and RNA of the girl. Because girls inherit an X chromosome from each of their parents (boys inherit a Y chromosome from their father), they also sequenced her mother and father. On average, about half of all X chromosomes active in a female come from the mother and the other half from the father.

“We now have the tools to significantly accelerate the diagnostic process, reducing the need for children to undergo multiple tests that can be emotionally and physically taxing for the entire family,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Co-Director of the Dorrance Center and the paper’s senior author.

Sequencing would reveal the proportion of X chromosomes, and if disproportionate, whether the more abundant of the two were damaged in some way, which often leads to X-linked genetic conditions.

“At the time of enrollment, we suspected the girl had a complex neurobehavioral condition, based on her attention deficit, and delays in development and learning,” said Dr. Vinodh Narayanan, Medical Director of the Dorrance Center. “Her brain MRI scans were normal. We needed to find out more — at the genetic level — about what might be causing her disorder.”

By sequencing the DNA and RNA, TGen investigators were able to precisely identify which cells contained active X chromosomes from the girl’s mother, which contained active X chromosomes from the father, in what proportions, and whether they were associated with any known disorders.

They discovered that the X chromosome from the father contained a segment shown to be associated with neurobehavioral conditions. Interestingly, however, the proportion of X chromosomes active in the girl’s cells skewed toward the normal X inherited from her mother. This skewing may have led to a milder, harder to diagnose condition undetected by conventional methods.

“This study shows the power sequencing holds when scanning for potential disease causing and disease-modifying genetic variations,” said Dr. Matt Huentelman, the other Co-Director of the Dorrance Center and an author of the PLOS ONE paper. “I’m most excited to see the pace at which TGen has pushed the genome sequencing technology to where it can help patients — today.”

TGen Research Associate Szabolcs Szelinger, the paper’s lead author, said: “With just a small bio sample, we are now able to provide a comprehensive evaluation of the effects that genetic variation has on patients, leading to highly personalized treatment options, while at the same time providing researchers with insights into the underlying molecular processes.”

Since opening in October 2013, TGen’s Dorrance Center for Rare Childhood Disorders Dorrance Center has enrolled nearly 300 families. And with the rapid decrease in sequencing costs and improved analytical methods, comprehensive, integrative sequencing approaches will likely be used more in the future. Information on the Dorrance Center is available at www.c4rcd.org.

Funding for the study came from the State of Arizona, the Stardust Foundation, and donations to the TGen Foundation.

In 2012, The Ben & Catherine Ivy Foundation awarded $10 million in grants for two groundbreaking brain cancer research projects at the Translational Genomics Research Institute (TGen). One of those projects has officially received the final regulatory approval from University of California, San Francisco, which means patient enrollment for the trial can begin.

In the $5-million-project, “Genomics Enabled Medicine in Glioblastoma Trial,” TGen and its clinical partners will lead first-in-patient clinical trial studies that will test promising new drugs that might extend the survival of GBM patients. This multi-part study will take place in clinics across the country and TGen laboratories.

“GBM is one of the top three fastest-killing cancers out there and it affects people of all ages,” said Catherine (Bracken) Ivy, founder and president of The Ben & Catherine Ivy Foundation. “It is critical that we fund research that will help patients live longer so we can study and treat brain cancer.”

The project begins with a pilot study of 15 patients, using whole genome sequencing to study their tumor samples to help physicians determine what drugs might be most beneficial.

To support molecularly informed clinical decisions, TGen labs also will examine genomic data from at least 536 past cases of glioblastoma, as well as tumor samples from new cases, developing tools that will produce more insight into how glioblastoma tumors grow and survive. TGen also will conduct a series of pioneering lab tests to measure cell-by-cell responses to various drugs.

“GBM is a disease that needs answers now, and we strongly believe those answers will be found in the genome,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Director of TGen’s Neurogenomics Division, and one of the projects principal investigators. “Identifying the genes that contribute to the survival of glioblastoma will provide valuable information on how to treat it, and may also lead to an improved understanding of what drives other cancers as well.”

To get new treatments to patients as quickly as possible, this five-year study will include a feasibility study involving up to 30 patients, followed by Phase II clinical trials with as many as 70 patients. TGen is teaming with the Ivy Early Phase Clinical Trials Consortium that includes: University of California, San Francisco; University of California, Los Angeles; the MD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; University of Utah; and the Dana-Farber/Harvard Cancer Center.

The results of these clinical trials should not only help the patients who join them, but also provide the data needed for FDA approval and availability of new drugs that could benefit tens of thousands of brain cancer patients in the future.

“Working with physicians, the project will aim to understand treatment in the context of the tumor’s molecular profile. We will have the opportunity to determine when combinations of drugs might be more effective than using a single drug, quickly identify which therapies don’t work, and accelerate discovery of ones that might prove promising for future development,” said Dr. John Carpten, TGen’s Deputy Director of Basic Science, Director of TGen’s Integrated Cancer Genomics Division, and another of the project’s principal investigators.

In addition to helping patients as quickly as possible, the project should significantly expand Arizona’s network of brain cancer experts.

The Ben & Catherine Ivy Foundation (Ivy Foundation) announced its 2012 grant recipients, which total more than $9 million in funding for brain cancer research. The Ivy Foundation is the largest privately funded brain cancer research foundation in North America. Catherine Ivy is the founder and president of the Ivy Foundation, which has a research funding focus on glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors in adults.

The Ivy Foundation awarded the following grants and/or provided funding in 2012:

“We are encouraged and remain strongly committed to moving the progress forward for patients diagnosed with brain cancer,” said Ivy. “The 2012 Ivy Foundation grant recipients are important strategic partners in our objective to double the life expectancy of people diagnosed with GBM within the next seven years.”